The present invention relates to a process for efficiently producing N-glycyltyrosine including N-glycyl-L-tyrosine dehydrate, which is one of the dipeptides useful as an ingredient of infusions. The invention also relates to N-glycyl-L-tyrosine dihydrate having specific crystal structures and processes for producing the same.
Amino acids and dipeptides thereof have been conventionally used as ingredients of infusions. N-Glycyl-L-tyrosine is a derivative prepared for the purpose of improving the solubility of L-tyrosine, which has very low water-solubility.
A process for producing N-glycyl-L-tyrosine is disclosed in Berichte der Deutschen Chemischen Gesellschaft, p. 2486 (1904). In the process, L-tyrosine is subjected to a reaction with 1.1 equivalents of chloroacetyl chloride and an aqueous solution of sodium hydroxide to obtain N-chloroacetyl-L-tyrosine, which is then made to react with aqueous ammonia to prepare N-glycyl-L-tyrosine. This process gives N-chloroacetyl-L-tyrosine, which is an intermediate for the synthesis of N-glycyl-L-tyrosine, in a 50% yield. The above literature also discloses a process in which L-tyrosine ethyl ester is made to react with 1.0 equivalent of chloroacetyl chloride to form N-chloroacetyl-L-tyrosine ethyl ester, which is then hydrolyzed to prepare N-chloroacetyl-L-tyrosine. In this process, the overall yield of N-chloroacetyl-L-tyrosine based on L-tyrosine ethyl ester is 91%, and that based on L-tyrosine is 77% as the yield in the step of conversion into ethyl ester from L-tyrosine is 85%. The process for producing N-glycyl-L-tyrosine via L-tyrosine ethyl ester is thus advantageous in respect of yield over the process in which L-tyrosine is directly chloroacetylated. However, when applied to the production on an industrial scale, the former process which requires the steps of esterification and hydrolysis is inefficient compared with the latter process requiring a smaller number of steps.
Another process for producing N-haloacetyl-L-tyrosine by direct haloacetylation of L-tyrosine is disclosed in Journal of Organic Chemistry, 18, 127(1953) and ibid., 18, 1546(1953). In this process, N-haloacetyl-L-tyrosine is produced by a reaction of L-tyrosine with 1-2 equivalents of chloroacetyl chloride in ethyl acetate under reflux. This reaction must be carried out under severe conditions. Further, the yield of the reaction product is 59% and thus the process is not satisfactory in respect of efficiency.
The crystal structure of N-glycyl-L-tyrosine dehydrate is disclosed in Crystal Structure Communication, 1, 301 (1972).
Under the circumstances, a one-step process for producing N-haloacetyltyrosine from tyrosine in high yields is desired for the production of N-glycyltyrosine using N-haloacetyltyrosine as an intermediate.
An object of the present invention is to efficiently produce N-haloacetyltyrosine and to efficiently produce N-glycyltyrosine by ammonolysis of N-haloacetyltyrosine using ammonia, if necessary in the presence of inorganic salts. Another object of the invention is to provide a process for producing N-glycyl-L-tyrosine dihydrate having specific crystal structures suitable for use as an ingredient of pharmaceutical compositions.